Tricyclic heterocyclic compound

ABSTRACT

Constitution 
     Tricyclic heterocyclyl compounds having a general formula (I): ##STR1## wherein: R 1  and R 2  each represents H, a lower alkyl or lower alkoxy group, a halogen atom or halogeno-lower alkyl; R 3  represents H or a lower alkyl group; R 4  represents a substituted phenyl or naphthyl group; R 5  represents H or a lower alkyl group; A represents a lower alkylene group; B represents an --O-- or --S-- group; and n is 0-1. 
     Effect 
     The compounds have an excellent activity in the inhibition of acyl-CoA: cholesterol acyltransferase (ACAT) and are useful for the treatment and prophylaxis of atherosclerosis.

This application is a 371 of PCT/JP92/01164 filed Sep. 11, 1992.

TECHNICAL FIELD

The present invention relates to tricyclic heterocyclyl compounds whichhave excellent activity in the inhibition of acyl-CoA: cholesterolacyltransferase.

BACKGROUND ART

Atherosclerosis is an important cause of ischemic cardiac insufficiencysuch as angina, myocardial infarction and the like. It has beenconsidered that a major cause of atherosclerosis is the accumulation ofcholesterol esters by foam cells which are present under the endodermiscell layer of blood vessels.

Inhibitors of acyl-CoA: cholesterol acyltransferase (hereinafterreferred as ACAT) inhibit the synthesis of cholesterol esters in thefoam cells and they diminish the accumulation of cholesterol esters,thereby inhibiting the formation and development of atherosclerosiscaused by the accumulation of cholesterol esters.

It has also been established that atherosclerosis is linked withhypercholesterolemia. Cholesterols in food are absorbed as freecholesterol in the intestinal mucosal cell tract, esterified by ACAT andthen enter the blood. Therefore, an inhibitor of ACAT will also preventa rise in the cholesterol concentration in the blood by inhibiting theabsorption of food cholesterol into the blood.

For this reason, compounds which are active in the inhibition of ACATare useful for the treatment and prophylaxis of atherosclerosis.

Tricyclic heterocyclyl compounds which inhibit ACAT are known and, forexample, a compound having the formula: ##STR2## has been disclosed inJapanese Patent Kokai Application No. Hei 2-6457.

However, it is still desired to develop a therapeutic agent having morepotent activity.

DISCLOSURE OF INVENTION

The present inventors have studied the synthesis of a series oftricyclic heterocyclyl compounds and the pharmacological activitythereof for many years. As a result, they have discovered that tricyclicheterocyclyl compounds having specific substituents exhibit excellentactivity in the inhibition of ACAT, and thus the present invention wasaccomplished.

CONSTITUTION OF INVENTION

Tricyclic heterocyclyl compounds according to the invention have ageneral formula I: ##STR3##

In the above formula, R¹ and R² are the same or different and eachrepresents a hydrogen atom, a lower alkyl group, a lower alkoxy group, ahalogen atom or a halogeno-lower alkyl group;

R³ represents a hydrogen atom or a lower alkyl group;

R⁴ represents a phenyl or naphthyl group, which has 1 to 3 substituentsand may optionally be condensed 5- or 6-membered heterocyclyl group (thesaid substituent represents a lower alkyl, halogeno-lower alkyl, loweralkoxy(lower alkyl), lower alkylthio(lower alkyl), aralkyl, loweralkenyl, lower alkoxy, aryloxy, aralkyloxy, lower alkylthio, arylthio,aralkylthio, carboxy, lower alkoxycarbonyl, lower alkylsulfinyl,arylsulfinyl, aralkylsulfinyl, lower alkylsulfonyl, arylsulfonyl oraralkylsulfonyl group, a halogen atom, a cyano or nitro group);

R⁵ represents a hydrogen atom or a lower alkyl group;

A represents a lower alkylene group;

B represents an oxygen or sulfur atom; and

n is 0 or 1.

Where R¹ and R² each represents a lower alkyl or halogeno-lower alkylgroup; R³ represents a lower alkyl group; a substituent of a phenyl ornaphthyl group represented by R⁴ is a lower alkyl, halogeno-lower alkyl,lower alkoxy(lower alkyl), lower alkylthio(lower alkyl), loweralkylthio, lower alkylsulfinyl or lower alkylsulfonyl group; and R⁵represents a lower alkyl group, the term "lower alkyl moiety" is heredefined mean a straight or branched C₁ -C₆ alkyl group such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl orhexyl, preferably a C₁ -C₄ alkyl group, and more preferably a methyl orethyl group.

Where R¹ and R² each represents a lower alkoxy; and a substituent of aphenyl or naphthyl group represented by R⁴ is a lower alkoxy, loweralkoxyalkyl or lower alkoxycarbonyl group, the alkyl moiety of the saidlower alkoxy group has the same meaning as the lower alkyl groupdescribed above.

Where R¹ and R² each represents a halogen atom or a halogeno-lower alkylgroup; and a substituent of a phenyl or naphthyl group represented by R⁴is a halogen atom or a halogeno-lower alkyl group, the term "halogen" isdefined to mean, for example, a fluorine, chlorine, bromine or iodineatom, preferably a fluorine or chlorine atom.

Where R⁴ represents 5- or 6-membered heterocyclyl group condensed with aphenyl group, it is a heterocyclyl group containing 1 or 2 hetero atomssuch as an oxygen, sulfur or nitrogen atom. Examples of suchheterocyclyl groups include, for example, furyl, dihydrofuryl, thienyl,dihydrothienyl, thiazolyl, dihydrothiazolyl, pyridyl ortetrahydropyridyl, preferably dihydrofuryl or dihydrothienyl group. Theheterocyclyl ring may optionally be substituted and examples of suchsubstituents include a lower alkyl group, preferably a methyl group.

Where a substituent of a phenyl or naphthyl group represented by R⁴ isan aralkyl, aryloxy, aralkyloxy, arylthio, aralkylthio, arylsulfinyl,aralkylsulfinyl, arylsulfonyl or aralkylsulfonyl group, the term "arylmoiety" is defined to mean a C₆ -C₁₀ aryl group such as phenyl, indanylor naphthyl, preferably a phenyl group. The phenyl ring may optionallybe substituted with 1 to 3 substituents (preferably 1); the saidsubstituent represents a lower alkyl (preferably a C₁ -C₄ alkyl group)or lower alkoxy group (preferably a C₁ -C₄ alkoxy group) or a halogenatom, particularly preferably a methyl, ethyl, methoxy or ethoxy group,a fluorine or chlorine atom.

Where a substituent of a phenyl or naphthyl group represented by R⁴ isan alkenyl group, it is a C₂ -C₆ alkenyl group such as, for example,vinyl , allyl, methallyl, 1-propenyl, 1-butenyl, 2-butenyl, 2-isobutenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl or 2-hexenyl, preferablya C₂ -C₄ alkenyl group, more preferably vinyl, allyl or 1-propenyl.

Examples of the said halogeno-lower alkyl group include, for example,fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,trichloromethyl, bromomethyl, iodomethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl,1-(fluoromethyl)ethyl, 3-chloropropyl, 4-fluorobutyl and 4-chlorobutylgroups, preferably trifluoromethyl and 2,2,2-trifluoroethyl groups.

Examples of the said lower alkoxy(lower alkyl) groups include, forexample, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,butoxymethyl, isobutoxymenhyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxypropyl, 3-ethoxypropyl, 1-ethoxymethylethyl, 4- ethoxybutyl,propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, 4-propoxybutyl,isopropoxymethyl, 2-isopropoxyethyl, butoxymethyl, 2-butoxyethyl,3-butoxypropyl and 4-butoxybutyl groups, preferably methoxymethyl,ethoxymethyl, propoxymethyl, butoxymethyl, isobutoxymethyl,2-methoxyethyl and 3-methoxypropyl groups.

Examples of the said lower alkylthio(lower alkyl) groups include: forexample, methylthiomethyl, 2-methylthioethyl, 3-methylthiopropyl,2-methylthio-1-methylethyl, 4-methylthiobutyl, ethylthiomethyl,2-ethylthioethyl, 3-ethylthiopropyl, 4-ethylthiobutyl, propylthiomethyl,2-propylthioethyl, 3-propylthiopropyl, 4-propylthiobutyl,isopropylthiomethyl, 2-isopropylthioethyl, butylthiomethyl,isobutylthiomethyl, 2-butylthioethyl, 3-butylthiopropyl and4-butylthiobutyl groups, preferably methylthiomethyl, 2-methylthioethyl,ethylthiomethyl, propylthiomethyl, isopropyl thiomethyl, butylthiomethyland isobutylthiomethyl groups.

Examples of the said aralkyl groups include: a C₇ -C₁₃ aralkyl groupssuch as, for example, benzyl, diphenylmethyl, phenethyl, 3-phenylpropyl,4-phenylbutyl, naphthylmethyl and 2-naphthylethyl groups, preferablybenzyl, phenethyl and 3-phenylpropyl groups.

Examples of the lower alkylene groups represented by A include: a C₁ -C₇alkylene group such as, for example, methylene, 1-methylmethylene,1,1-dimethylmethylene, ethylene, trimethylene, 1-methylethylene,tetramethylene, pentamethylene, 1-butylmethylene, hexamethylene andheptamethylene groups, preferably a C₁ -C₄ alkylene group, morepreferably methylene and 1-methylmethylene groups.

R⁴ represents preferably a phenyl group having 2 or 3 substituents (thesaid 2 substituents are located in an ortho position with respect toeach other) or a phenyl group condensed with an optionally C₁ -C₄alkyl-substituted dihydrofuryl or dihydrothienyl group; more preferablya phenyl group having 2 or 3 substituents (the said 2 substituents arelocated in an ortho position with respect to each other).

Preferred examples of the substituents involved in R⁴ include: C₁ -C₄alkyl, halogeno(C₁ -C₄ alkyl) [particularly trifluoromethyl,2-fluoroethyl, 3-fluoropropyl and 1-(fluoromethyl)ethyl groups], C₁ -C₄alkoxy(C₁ -C₄ alkyl), C₁ -C₄ alkylthio(C₁ -C₄ alkyl), benzyl, phenethyl,3-phenylpropyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, C₆ -aryloxy, C₇ -C₁₀aralkyloxy, C₁ -C₄ alkylthio, C₆ -C₁₀ arylthio, C₇ -C₁₀ aralkylthio, C₁-C₄ alkoxycarbonyl, C₁ -C₄ alkylsulfinyl and C₁ -C₄ alkylsulfonylgroups, a halogen atom and a nitro group; more preferably C₁ -C₄ alkyl,C₁ -C₄ alkoxy(C₁ -C₄ alkyl), C₁ -C₄ alkylthio(C₁ -C₄ alkyl), C₂ -C₄alkenyl, C₁ -C₄ alkoxy, C₇ -C₁₀ aralkyloxy, C₁ -C₄ alkylthio, C₆-arylthio, benzylthio, phenethylthio, 3-phenylpropylthio,methoxycarbonyl, methylsulfinyl and methanesulfonyl groups, a halogenatom and a nitro group; particularly preferably C₁ -C₄ alkyl[particularly methyl, ethyl, propyl and isopropyl groups], C₁ -C₄alkoxy-(C₁ -C₄ alkyl) [particularly methoxymethyl, methoxyethyl,ethoxymethyl and propoxymethyl group], C₁ -C₄ alkylthio(C₁ -C₄ alkyl){particularly methylthiomethyl, methylthioethyl, ethylthiomethyl andpropiothiomethyl groups}, C₂ -C₄ alkenyl {particularly vinyl and allylgroups}, C₁ -C₄ alkoxy {particularly methoxy, ethoxy, propoxy andisopropoxy groups}, C₇ -C₉ aralkyloxy {particularly benzyloxy andphenethyloxy groups}, C₁ -C₄ alkylthio {particularly methylthio,ethylthio, propylthio and isopropylthio groups}, phenyltyhio and C₇ -C₉aralkylthio groups {particularly benzylthio and phenethylthio groups}, ahalogen atom {particularly a chlorine atom}and a nitro group; and mostpreferably ethyl, propyl, isopropyl, methoxymethyl, methylthiomethyl,methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, methylthio, ethylthio,propylthio, isopropylthio and phenylthio groups.

The compounds of formula (I) can exist in the form optical isomers dueto the presence of an asymmetric carbon atom. The present inventioncovers not only mixtures of the isomers but also the individual isomers.

The preferred compounds of general formula (I) are those in which:

(1) R¹ and R² each represents a hydrogen atom, a methyl, ethyl, methoxyor ethoxy group, a fluorine or chlorine atom;

(2) R¹ and R² each represents a hydrogen atom;

(3) R³ represents a hydrogen atom, a methyl or ethyl group;

(4) R³ represents a hydrogen atom or a methyl group;

(5) R⁴ represents a phenyl group which has 2 or 3 substituents and mayoptionally be condensed with an optionally C₁ -C₄ alkyl-substituteddihydrofuryl or dihydrothienyl ring [the 1 or 2 substituents are locatedin an ortho position and each is a C₁ -C₄ alkyl, halogeno(C₁ -C₄ alkyl){particularly a trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl or1-(fluoromethyl)ethyl group}, C₁ -C₄ alkoxy(C₁ -C₄ alkyl), C₁ -C₄alkylthio(C₁ -C₄ alkyl), benzyl, phenethyl, 3-phenylpropyl, C₂ -C₄alkenyl, C₁ -C₄ alkoxy, C₆ -aryloxy, C₇ -C₁₀ aralkyloxy, C₁ -C₄alkylthio, C₆ -C₁₀ arylthio, C₇ -C₁₀ aralkylthio, C₁ -C₄ alkoxycarbonyl,C₁ -C₄ alkylsulfinyl or C₁ -C₄ alkylsulfonyl group, a halogen atom, or anitro group];

(6) R⁴ represents a phenyl group which has 2 or 3 substituents and mayoptionally be condensed with an optionally C₁ -C₄ alkyl-substituteddihydrofuryl ring [the said 2 substituents are located in an orthoposition with respect to each other and each is a C₁ -C₄ alkyl, C₁ -C₄alkoxy(C₁ -C₄ alkyl), C₁ -C₄ alkylthio(C₁ -C₄ alkyl), C₂ -C₄ alkenyl, C₁-C₄ alkoxy, C₇ -C₁₀ aralkyloxy, C₁ -C₄ alkylthio, C₆ -arylthio,benzylthio, phenethylthio, 3-phenylpropylthio, methoxycarbonyl,methylsulfinyl or methanesulfonyl group, a halogen atom or a nitrogroup];

(7) R⁴ represents a phenyl group which has 2 or 3 substituents [2 of thesaid substituents are located in an ortho position and each is a C₁ -C₄alkyl {particularly a methyl, ethyl, propyl or isopropyl group}, C₁ -C₄alkoxy(C₁ -C₄ alkyl) {particularly a methoxymethyl, methoxyethyl,ethoxymethyl or ethoxyethyl group}, C₁ -C₄ alkylthio(C₁ -C₄ alkyl){particularly a methylthiomethyl, methylthioethyl, ethylthiomethyl orethylthioethyl group}, C₂ -C₄ alkenyl {particularly a vinyl or allylgroup}, C₁ -C₄ alkoxy {particularly a methoxy, ethoxy, propoxy orisopropoxy group}, C₇ -C₉ aralkyloxy {particularly a benzyloxy orphenethyloxy group}, C₁ -C₄ alkylthio {particularly a methylthio,ethylthio, propylthio or isopropylthio group}, phenylthio or C₇ -C₉aralkylthio group {particularly a benzylthio or phenethylthio group}, ahalogen atom {particularly a chlorine atom) or a nitro group];

(8) R⁵ represents a hydrogen atom, a methyl or ethyl group;

(9) R⁵ represents a hydrogen atom;

(10) A represents a C₁ -C₄ alkylene group;

(11) A represents a C₁ -C₂ alkylene group;

(12) B represents an oxygen atom; and

(13) n is 0.

Examples of the compounds of the said general formula (I) in accordancewith the present invention are listed and the compounds of formula (I-1)and formula (I-2) are illustrated in Table 1 and 2, respectively. Suchexamples are not to be construed as being limitative of the invention.

                                      TABLE 1                                     __________________________________________________________________________     ##STR4##                            (I-1)                                     ##STR5##                            (I-2)                                    Cmpd. No.                                                                           R.sup.1                                                                            R.sup.3                                                                          R.sup.4        R.sup.5                                                                          A     n                                       __________________________________________________________________________    1-1   H    H  2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-2   H    H  2,6-di-EtPh    H  CH.sub.2                                                                            0                                       1-3   H    H  2,6-di-MePh    H  CH.sub.2                                                                            0                                       1-4   H    H  2-Et-6-iPrPh   H  CH.sub.2                                                                            0                                       1-5   H    H  2-Me-6-PnPh    H  CH.sub.2                                                                            0                                       1-6   H    H  2-Et-6-PnPh    H  CH.sub.2                                                                            0                                       1-7   H    H  2-Et-6-BuPh    H  CH.sub.2                                                                            0                                       1-8   H    H  2-Et-6-PrPh    H  CH.sub.2                                                                            0                                       1-9   H    H  2-Me-6-PrPh    H  CH.sub.2                                                                            0                                       1-10  H    H  2-Me-6-BuPh    H  CH.sub.2                                                                            0                                       1-11  H    H  2,6-di-PrPh    H  CH.sub.2                                                                            0                                       1-12  H    H  2-Et-6-MeSCH.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-13  H    H  2-Et-6-EtSCH.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-14  H    H  2-Me-6-EtSCH.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-15  H    H  2-Me-6-MeSCH.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-16  H    H  2-iPr-6-MeSCH.sub.2 Ph                                                                       H  CH.sub.2                                                                            0                                       1-17  H    H  2-iPr-6-EtSCH.sub.2 Ph                                                                       H  CH.sub.2                                                                            0                                       1-18  H    H  2-Me-6-MeOPh   H  CH.sub.2                                                                            0                                       1-19  H    H  2-Me-6-BuOPh   H  CH.sub.2                                                                            0                                       1-20  H    H  2-Me-6-EtOPh   H  CH.sub.2                                                                            0                                       1-21  H    H  2-Me-6-PrOPh   H  CH.sub.2                                                                            0                                       1-22  H    H  2-Me-6-iPrOPh  H  CH.sub.2                                                                            0                                       1-23  H    H  2-Et-6-MeOPh   H  CH.sub.2                                                                            0                                       1-24  H    H  2-Et-6-EtOPh   H  CH.sub.2                                                                            0                                       1-25  H    H  2-Et-6-PrOPh   H  CH.sub.2                                                                            0                                       1-26  H    H  2-Et-6-iPrOPh  H  CH.sub.2                                                                            0                                       1-27  H    H  2-Et-6-BuOPh   H  CH.sub.2                                                                            0                                       1-28  H    H  2-Vin-6-MeOPh  H  CH.sub.2                                                                            0                                       1-29  H    H  2-Vin-6-EtOPh  H  CH.sub.2                                                                            0                                       1-30  H    H  2-Vin-6-iPrOPh H  CH.sub.2                                                                            0                                       1-31  H    H  2-Vin-6-PrOPh  H  CH.sub.2                                                                            0                                       1-32  H    H  2-Vin-6-BuOPh  H  CH.sub.2                                                                            0                                       1-33  H    H  2,4,6-tri-MeOPh                                                                              H  CH.sub.2                                                                            0                                       1-34  H    H  2-NO.sub.2 -6PhCH.sub.2 OPh                                                                  H  CH.sub.2                                                                            0                                       1-35  H    H  2-NO.sub.2 -6-EtPh                                                                           H  CH.sub.2                                                                            0                                       1-36  H    H  2-NO.sub.2 -6-MePh                                                                           H  CH.sub.2                                                                            0                                       1-37  H    H  2-Me-6PhOPh    H  CH.sub.2                                                                            0                                       1-38  H    H  2-Et-6PhOPh    H  CH.sub.2                                                                            0                                       1-39  H    H  2-iBut-6-iPrOPh                                                                              H  CH.sub.2                                                                            0                                       1-40  H    H  2-iBut-6-PrOPh H  CH.sub.2                                                                            0                                       1-41  H    H  2-iBut-6-MePh  H  CH.sub.2                                                                            0                                       1-42  H    H  2-iBut-6-EtPh  H  CH.sub.2                                                                            0                                       1-43  H    H  2-Vin-6-MePh   H  CH.sub.2                                                                            0                                       1-44  H    H  2-Vin-6-EtPh   H  CH.sub.2                                                                            0                                       1-45  H    H  2-Cl-6-CO.sub.2 MePh                                                                         H  CH.sub.2                                                                            0                                       1-46  H    H  2,6-di-ClPh    H  CH.sub.2                                                                            0                                       1-47  H    H  2-F-6-ClPh     H  CH.sub.2                                                                            0                                       1-48  H    H  2,6-di-FPh     H  CH.sub.2                                                                            0                                       1-49  H    H  2-F-6-MePh     H  CH.sub.2                                                                            0                                       1-50  H    H  2-F-6-EtPh     H  CH.sub.2                                                                            0                                       1-51  H    H  2-F-6-iPrPh    H  CH.sub.2                                                                            0                                       1-52  H    H  2-Cl-6-MePh    H  CH.sub.2                                                                            0                                       1-53  H    H  2-Cl-6-EtPh    H  CH.sub.2                                                                            0                                       1-54  H    H  2-Cl-6-iPrPh   H  CH.sub.2                                                                            0                                       1-55  H    H  2-Cl-6-MeSPh   H  CH.sub.2                                                                            0                                       1-56  H    H  2-Cl-6-EtSPh   H  CH.sub.2                                                                            0                                       1-57  H    H  2-Cl-6-iPrSPh  H  CH.sub.2                                                                            0                                       1-58  H    H  2-Cl-6-PrSPh   H  CH.sub.2                                                                            0                                       1-59  H    H  2-Cl-6-iPnSPh  H  CH.sub.2                                                                            0                                       1-60  H    H  2-Cl-6-BuSPh   H  CH.sub.2                                                                            0                                       1-61  H    H  2-Cl-6PhSPh    H  CH.sub.2                                                                            0                                       1-62  H    H  2-Cl-6-(p-TolS)Ph                                                                            H  CH.sub.2                                                                            0                                       I-63  H    H  2-Cl-6-(p-MeOPhS)Ph                                                                          H  CH.sub.2                                                                            0                                       1-64  H    H  2-Cl-6-(o-ClPhS)Ph                                                                           H  CH.sub.2                                                                            0                                       1-65  H    H  2-F-6-MeSPh    H  CH.sub.2                                                                            0                                       1-66  H    H  2-F-6-EtSPh    H  CH.sub.2                                                                            0                                       1-67  H    H  2-F-6-iPrSPh   H  CH.sub.2                                                                            0                                       1-68  H    H  2-F-6-PrSPh    H  CH.sub.2                                                                            0                                       1-69  H    H  2-F-6-BuSPh    H  CH.sub.2                                                                            0                                       1-70  H    H  2-F-6-iPnSPh   H  CH.sub.2                                                                            0                                       1-71  H    H  2-F-6PhCH.sub.2 SPh                                                                          H  CH.sub.2                                                                            0                                       1-72  H    H  2-F-6PhCH.sub.2 CH.sub.2 SPh                                                                 H  CH.sub.2                                                                            0                                       1-73  H    H  2-Cl-6PhCH.sub.2 SPh                                                                         H  CH.sub.2                                                                            0                                       1-74  H    H  2-Cl-6PhCH.sub.2 CH.sub.2 SPh                                                                H  CH.sub.2                                                                            0                                       1-75  H    H  2-Cl-6-MeOPh   H  CH.sub.2                                                                            0                                       1-76  H    H  2-Cl-6-EtOPh   H  CH.sub.2                                                                            0                                       1-77  H    H  2-Cl-6-iPrOPh  H  CH.sub.2                                                                            0                                       1-78  H    H  2-Cl-6-PrOPh   H  CH.sub.2                                                                            0                                       1-79  H    H  2-F-6-MeOPh    H  CH.sub.2                                                                            0                                       1-80  H    H  2-F-6-EtOPh    H  CH.sub.2                                                                            0                                       1-81  H    H  2-F-6-iPrOPh   H  CH.sub.2                                                                            0                                       1-82  H    H  2-F-6-PrOPh    H  CH.sub.2                                                                            0                                       1-83  H    H  2-F-6PhCH.sub.2 OPh                                                                          H  CH.sub.2                                                                            0                                       1-84  H    H  2-Cl-6PhCH.sub.2 OPh                                                                         H  CH.sub.2                                                                            0                                       1-85  H    H  2-F-6PhOPh     H  CH.sub.2                                                                            0                                       1-86  H    H  2-Cl-6PhOPh    H  CH.sub.2                                                                            0                                       1-87  H    H  2-Me-6PhOPh    H  CH.sub.2                                                                            0                                       1-88  H    H  2-Et-6PhOPh    H  CH.sub.2                                                                            0                                       1-89  H    H  2-Me-6PhCH.sub.2 OPh                                                                         H  CH.sub.2                                                                            0                                       1-90  H    H  2-Et-6PhCH.sub.2 OPh                                                                         H  CH.sub.2                                                                            0                                       1-91  H    H  2-Pr-6PhCH.sub.2 OPh                                                                         H  CH.sub.2                                                                            0                                       1-92  H    H  2-iPr-6PhCH.sub.2 OPh                                                                        H  CH.sub.2                                                                            0                                       1-93  H    H  2-MeO-6PhCH.sub.2 OPh                                                                        H  CH.sub.2                                                                            0                                       1-94  H    H  2-EtO-6PhCH.sub.2 OPh                                                                        H  CH.sub.2                                                                            0                                       1-95  H    H  2,6-di-iPrOPh  H  CH.sub.2                                                                            0                                       1-96  H    H  2,6-di-EtOPh   H  CH.sub.2                                                                            0                                       1-97  H    H  2,6-di-MeOPh   H  CH.sub.2                                                                            0                                       1-98  H    H  2,6-di-iPrPh   H  CH(Me)                                                                              0                                       1-99  H    H  2,6-di-EtPh    H  CH(Me)                                                                              0                                       1-100 H    H  2-Et-6-MeOPh   H  CH(Me)                                                                              0                                       1-101 H    H  2-Et-6-EtOPh   H  CH(Me)                                                                              0                                       1-102 H    H  2-Et-6-iPrOPh  H  CH(Me)                                                                              0                                       1-103 H    H  2-Et-6PhOPh    H  CH(Me)                                                                              0                                       1-104 H    H  2-Et-6PhCH.sub.2 OPh                                                                         H  CH(Me)                                                                              0                                       1-105 H    H  2-Et-6-MeSPh   H  CH(Me)                                                                              0                                       1-106 H    H  2-Et-6-EtSPh   H  CH(Me)                                                                              0                                       1-107 H    H  2-Et-6-iPrSPh  H  CH(Me)                                                                              0                                       1-108 H    H  2-Et-6-PrSPh   H  CH(Me)                                                                              0                                       1-109 H    H  2-Et-6PhSPh    H  CH(Me)                                                                              0                                       1-110 H    H  2-Et-6PhCH.sub.2 SPh                                                                         H  CH(Me)                                                                              0                                       1-111 H    H  2-Me-6-iPrSPh  H  CH(Me)                                                                              0                                       1-112 H    H  2-Me-6-EtSPh   H  CH(Me)                                                                              0                                       1-113 H    H  2-Me-6-MeSPh   H  CH(Me)                                                                              0                                       1-114 H    Me 2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-115 H    Me 2,6-di-EtPh    H  CH.sub.2                                                                            0                                       1-116 H    Me 2-Et-6-MeOPh   H  CH.sub.2                                                                            0                                       1-117 H    Me 2-Et-6-EtOPh   H  CH.sub.2                                                                            0                                       1-118 H    Me 2-Et-6-iPrOPh  H  CH.sub.2                                                                            0                                       1-119 H    Me 2-Et-6PhOPh    H  CH.sub.2                                                                            0                                       1-120 H    Me 2-Et-6PhCH.sub.2 OPh                                                                         H  CH.sub.2                                                                            0                                       1-121 H    Me 2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-122 H    Me 2-Et-6-EtSPh   H  CH.sub.2                                                                            0                                       1-123 H    Me 2-Et-6-iPrSPh  H  CH.sub.2                                                                            0                                       1-124 H    Me 2-Et-6-PrSPh   H  CH.sub.2                                                                            0                                       1-125 H    Me 2-Et-6PhSPh    H  CH.sub.2                                                                            0                                       1-126 H    Me 2-Et-6PhCH.sub.2 SPh                                                                         H  CH.sub.2                                                                            0                                       1-127 H    Me 2-Et-6-MeSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-128 H    Me 2-Et-6-EtSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-129 H    Me 2-Et-6-iPrSO.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-130 H    Me 2-Et-6-PrSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-131 H    Me 2-Et-6PhCH.sub.2 SO.sub.2 Ph                                                                 H  CH.sub.2                                                                            0                                       1-132 H    Me 2-Me-6-EtPh    H  CH.sub.2                                                                            0                                       1-133 H    H  2-Et-6-MeSO.sub.2 Ph                                                                         H  CH(Me)                                                                              0                                       1-134 H    H  2-Et-6-EtSO.sub.2 Ph                                                                         H  CH(Me)                                                                              0                                       1-135 H    H  2-Et-6-iPrSO.sub.2 Ph                                                                        H  CH(Me)                                                                              0                                       1-136 H    H  2-Cl-6-MeSO.sub.2 Ph                                                                         H  CH(Me)                                                                              0                                       1-137 H    H  2-Cl-6-MeSPh   H  CH(Me)                                                                              0                                       1-138 H    H  2-F-6-MeSPh    H  CH(Me)                                                                              0                                       1-139 H    H  2-F-6-MeSO.sub.2 Ph                                                                          H  CH(Me)                                                                              0                                       1-140 H    H  2-F-6-MeSO.sub.2 Ph                                                                          H  CH(Et)                                                                              0                                       1-141 H    H  2-F-6-MeSPh    H  CH(Et)                                                                              0                                       1-142 H    H  2-F-6-EtSPh    H  CH(Et)                                                                              0                                       1-143 H    H  2-F-6-iPrSPh   H  CH(Et)                                                                              0                                       1-144 H    Me 2,6-di-iPrPh   H  CH(Me)                                                                              0                                       1-145 H    Me 2,6-di-EtPh    H  CH(Me)                                                                              0                                       1-146 H    Me 2-Et-6-MeSPh   H  CH(Me)                                                                              0                                       1-147 H    Me 2-Et-6-MeSO.sub.2 Ph                                                                         H  CH(Me)                                                                              0                                       1-148 H    Me 2-Et-6-MeOPh   H  CH(Me)                                                                              0                                       1-149 H    Me 2-Et-6-EtOPh   H  CH(Me)                                                                              0                                       1-150 H    Me 2-Et-6-iPrOPh  H  CH(Me)                                                                              0                                       1-151 H    Me 2-Et-6PhCH.sub.2 OPh                                                                         H  CH(Me)                                                                              0                                       1-152 H    Me 2-Et-6-EtSPh   H  CH(Me)                                                                              0                                       1-153 H    Me 2-Et-6-EtSO.sub.2 Ph                                                                         H  CH(Me)                                                                              0                                       1-154 H    Me 2-Et-6-iPrSPh  H  CH(Me)                                                                              0                                       1-155 H    Bu 2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-156 H    Bu 2,6-di-EtPh    H  CH.sub.2                                                                            0                                       1-157 H    Bu 2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-158 H    Bu 2-Et-6-MeSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-159 H    Pr 2,6-di-EtPh    H  CH.sub.2                                                                            0                                       1-160 H    Pr 2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-161 H    Pr 2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-162 H    Me 2,6-di-iPrPh   H  C(Me).sub.2                                                                         0                                       1-163 H    Me 2,6-di-EtPh    H  C(Me).sub.2                                                                         0                                       1-164 H    H  2,6-di-iPrPh   H  CH.sub.2                                                                            1                                       1-165 H    H  2,6-di-EtPh    H  CH.sub.2                                                                            1                                       1-166 H    H  2-Et-6-MeSPh   H  CH.sub.2                                                                            1                                       1-167 H    H  2-Et-6-MeSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            1                                       1-168 H    H  2-Et-6-iPrOPh  H  CH.sub.2                                                                            1                                       1-169 H    Me 2,6-di-iPrPh   H  CH.sub.2                                                                            1                                       1-170 H    Me 2,6-di-EtPh    H  CH.sub.2                                                                            1                                       1-171 H    Me 2-Et-6-MeSPh   H  CH.sub.2                                                                            1                                       1-172 H    H  2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-173 H    H  2-iPr-6-MeSPh  H  CH.sub.2                                                                            0                                       1-174 H    H  2-Pr-6-MeSPh   H  CH.sub.2                                                                            0                                       1-175 H    H  2-Bu-6-MeSPh   H  CH.sub.2                                                                            0                                       1-176 H    H  2-iPn-6-MeSPh  H  CH.sub.2                                                                            0                                       1-177 H    H  2-Et-6-MeSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-178 H    H  2-Et-6-MeSOPh  H  CH.sub.2                                                                            0                                       1-179 H    H  2-iPr-6-EtSPh  H  CH.sub.2                                                                            0                                       1-180 H    H  2-iPr-6-EtSO.sub.2 Ph                                                                        H  CH.sub.2                                                                            0                                       1-181 H    H  2-Et-6-EtSPh   H  CH.sub.2                                                                            0                                       1-182 H    H  2-Et-6-EtSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-183 H    H  2-Me-6-EtSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-184 H    H  2-Me-6-EtSOPh  H  CH.sub.2                                                                            0                                       1-185 H    H  2-Et-6PhCH.sub.2 SPh                                                                         H  CH.sub.2                                                                            0                                       1-186 H    H  2-Et-6PhCH.sub.2 SO.sub.2 Ph                                                                 H  CH.sub.2                                                                            0                                       1-187 H    H  2-Et-6PhSPh    H  CH.sub.2                                                                            0                                       1-188 H    H  2-Et-6PhSO.sub.2 Ph                                                                          H  CH.sub.2                                                                            0                                       1-189 H    H  2-Et-6PhCH.sub.2 CH.sub.2 SPh                                                                H  CH.sub.2                                                                            0                                       1-190 H    H  2-Et-6PhCH.sub.2 CH.sub.2 SO.sub.2 Ph                                                        H  CH    0                                       1-191 H    H  2-Me-6PhCH.sub.2 SPh                                                                         H  CH.sub.2                                                                            0                                       1-192 H    H  2-Me-6PhCH.sub.2 SO.sub.2 Ph                                                                 H  CH.sub.2                                                                            0                                       1-193 H    H  2-MeOCH.sub.2 -6-MeSPh                                                                       H  CH.sub.2                                                                            0                                       1-194 H    H  2-MeOCH.sub.2 -6-MeSO.sub.2 Ph                                                               H  CH.sub.2                                                                            0                                       1-195 H    H  2-MeOCH.sub.2 -6-EtSPh                                                                       H  CH.sub.2                                                                            0                                       1-196 H    H  2-MeOCH.sub.2 -6-EtSO.sub.2 Ph                                                               H  CH.sub.2                                                                            0                                       1-197 H    H  2-MeOCH.sub.2 -6-iPrSO.sub.2 Ph                                                              H  CH.sub.2                                                                            0                                       1-198 H    H  2-MeOCH.sub.2 -6-iPrSPh                                                                      H  CH.sub.2                                                                            0                                       1-199 H    H  2-MeOCH.sub.2 -6PhSPh                                                                        H  CH.sub.2                                                                            0                                       1-200 H    H  2-MeOCH.sub.2 -6PhSO.sub.2 Ph                                                                H  CH.sub.2                                                                            0                                       1-201 H    H  2-EtOCH.sub.2 -6-MeSPh                                                                       H  CH.sub.2                                                                            0                                       1-202 H    H  2-EtOCH.sub.2 -6-MeSO.sub.2 Ph                                                               H  CH.sub.2                                                                            0                                       1-203 H    H  2-EtOCH.sub.2 -6-EtSPh                                                                       H  CH.sub.2                                                                            0                                       1-204 1-MeO                                                                              H  2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-205 2-MeO                                                                              H  2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-206 3-MeO                                                                              H  2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-207 4-MeO                                                                              H  2,6-di-iPrPh   H  CH.sub.2                                                                            0                                       1-208 1-MeO                                                                              H  2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-209 2-MeO                                                                              H  2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-210 3-MeO                                                                              H  2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-211 4-MeO                                                                              H  2-Et-6-MeSPh   H  CH.sub.2                                                                            0                                       1-212 2-MeO                                                                              H  2-Et-6-MeOPh   H  CH.sub.2                                                                            0                                       1-213 2-MeO                                                                              H  2-Et-6-EtSPh   H  CH.sub.2                                                                            0                                       1-214 2-MeO                                                                              H  2-Et-6-iPrSPh  H  CH.sub.2                                                                            0                                       1-215 H    H  2-EtOCH.sub.2 -6-EtSO.sub.2 Ph                                                               H  CH.sub.2                                                                            0                                       1-216 H    H  2-EtOCH.sub.2 -6PhSPh                                                                        H  CH.sub.2                                                                            0                                       1-217 H    H  2-EtOCH.sub.2 -6PhSO.sub.2 Ph                                                                H  CH.sub.2                                                                            0                                       1-218 H    H  2-MeOCH.sub.2 -6PhCH.sub.2 SPh                                                               H  CH.sub.2                                                                            0                                       1-219 H    H  2-MeOCH.sub.2 -6PhCH.sub.2 SO.sub.2 Ph                                                       H  CH.sub.2                                                                            0                                       1-220 H    Me 2-MeOCH.sub.2 -6-MeSPh                                                                       H  CH.sub.2                                                                            0                                       1-221 H    Me 2-MeOCH.sub.2 -6-EtSPh                                                                       H  CH.sub.2                                                                            0                                       1-222 H    Me 2-MeOCH.sub.2 -6-MeSO.sub.2 Ph                                                               H  CH.sub.2                                                                            0                                       1-223 H    H  2,6-di-MeSPh   H  CH.sub.2                                                                            0                                       1-224 H    H  2,6-di-EtSPh   H  CH.sub.2                                                                            0                                       1-225 H    H  2,6-di-MeSO.sub.2 Ph                                                                         H  CH.sub.2                                                                            0                                       1-226 H    H  2,6-di-Me-Bezf H  CH.sub.2                                                                            0                                       1-227 H    H  2,2,6-tri-Me-Bezf                                                                            H  CH.sub.2                                                                            0                                       1-228 H    Me 2,6-di-Me-Bezf H  CH.sub.2                                                                            0                                       1-229 H    H  2-Me-6-Et-Bezf H  CH.sub.2                                                                            0                                       1-230 H    H  2,2-di-Me-6-Et-Bezf                                                                          H  CH.sub.2                                                                            0                                       1-231 H    Me 2-Me-6-Et-Bezf H  CH.sub.2                                                                            0                                       1-232 H    Me 2,2-di-Me-6-Et-Bezf                                                                          H  CH.sub.2                                                                            0                                       1-233 H    H  2,2-di-Me-6-Et-Bezf                                                                          H  CH.sub.2                                                                            1                                       1-234 H    H  2-Cl-6-CH.sub.2 OMePh                                                                        H  CH.sub.2                                                                            0                                       1-235 H    H  2-Cl-6-CH.sub.2 OPrPh                                                                        H  CH.sub.2                                                                            0                                       1-236 H    H  2-Cl-6-CH.sub.2 OEtPh                                                                        H  CH.sub.2                                                                            0                                       1-237 H    H  2-Cl-6-CH.sub.2 OBuPh                                                                        H  CH.sub.2                                                                            0                                       1-238 H    H  2-Cl-6-CH.sub.2 OPnPh                                                                        H  CH.sub.2                                                                            0                                       __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Cmpd. No.                                                                             R.sup.1                                                                              R.sup.3                                                                              R.sup.4       R.sup.5                                                                           A    n                                ______________________________________                                        2-1     3-Cl   H      2,6-di-iPr--Ph                                                                              H   CH.sub.2                                                                           0                                2-2     3-Cl   H      2,6-di-Et--Ph H   CH.sub.2                                                                           0                                2-3     H      H      2,6-di-iPr--Ph                                                                              H   CH.sub.2                                                                           0                                2-4     H      H      2,6-di-Et--Ph H   CH.sub.2                                                                           0                                2-5     H      H      2-Et-6-MeS--Ph                                                                              H   CH.sub.2                                                                           0                                2-6     H      H      2-Et-6-iPrO--Ph                                                                             H   CH.sub.2                                                                           0                                2-7     H      H      2,6-di-Me--Bezf                                                                             H   CH.sub.2                                                                           0                                2-8     H      H      2-Me-6-Et--Bezf                                                                             H   CH.sub.2                                                                           0                                2-9     H      H      2,2-di-Me-6-Et--Bezf                                                                        H   CH.sub.2                                                                           0                                2-10    H      Me     2,6-di-iPr--Ph                                                                              H   CH.sub.2                                                                           0                                2-11    H      Me     2,6-di-Et--Ph H   CH.sub.2                                                                           0                                2-12    H      H      2-Cl-6-MeOCH.sub.2 --Ph                                                                     H   CH.sub.2                                                                           0                                2-13    H      H      2-Cl-6-EtOCH.sub.2 --Ph                                                                     H   CH.sub.2                                                                           0                                2-14    H      H      2-SMe-6-MeOCH.sub.2 --Ph                                                                    H   CH.sub.2                                                                           0                                ______________________________________                                    

In the above Tables 1 and 2 the abbreviations used have the followingsignificance.

Bezf: 2,3-dihydrobenzo[b]furan-7-yl

Bu: butyl

But: butenyl

Et: ethyl

Me: methyl

Ph: phenyl

Pn: pentyl

Pr: propyl

Tol: tolyl

Vin: vinyl

The compounds in accordance with the present invention can easily beprepared by the following method.

Method A ##STR6##

In the above formulae, R¹, R², R³, R⁴, R⁵, A, B and n are as definedabove.

Method A involves a method for preparing a compound of formula (I) ofthe invention.

Step A1 involves the preparation of a compound of formula (I) and can beaccomplished by reacting a carboxylic acid compound having a generalformula (II) or its reactive derivative with an amine compound having ageneral formula (III). The step is carried out by using a method such asan acid halide, mixed acid anhydride, activated ester and condensationreaction methods.

Using an acid halide method, the desired compound of a formula (I) canbe prepared by reacting a carboxylic acid having a formula (II) with ahalogenating agent to form an acid halide and then reacting with acompound of formula (III) in an inert solvent in the presence or absenceof a base.

Examples of the acid-halogenating agents used include, for example,thionyl chloride, oxalyl chloride, phosphorus pentachloride and thionylbromide, preferably chloride and oxalyl chloride.

Examples of the bases used include, for example, organic amines such astriethylamine, N-Methylmorpholine, pyridine, 4-dimethylaminopyridine,2,6-lutidine and N,N-dimethylaniline; alkaline metal bicarbonates suchas sodium bicarbonate or potassium bicarbonate; and alkaline metalcarbonates such as sodium carbonate or potassium carbonate; preferablyorganic amines.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Examples ofsuch solvents include: for example, hydrocarbons such as hexane,cyclohexane, benzene, toluene or xylene; halogenated hydrocarbons suchas dichloromethane, 1,2-dichloroethane or carbon tetrachloride; etherssuch as ether, tetrahydrofuran or dioxane; ketones such as acetone;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone or hexamethylphosphoramide; sulfoxides such asdimethyl sulfoxide; preferably hydrocarbons, halogenated hydrocarbons,ethers and amides; and particularly preferably halogenated hydrocarbons.

The reaction temperature depends upon the starting compounds of formula(II) and (III), the nature of the solvent used and the like, but bothreactions of a compound (II) with a halogenating agent and those of theresulting acid halide with a compound (III) are usually carried out at atemperature of -20° C. to 100° C. Preferably the reaction of a compound(II) with a halogenating agent is carried out at a temperature of 0° C.to 30° C. and the reaction of the resulting acid halide with a compound(III) at a temperature of 0° C. to 50° C. Although the time required forthe reaction depends upon the reaction temperature and the like, bothreactions complete within a period of 30 minutes to 24 hours. Preferablythe first reaction takes from 1 to 10 hours and the subsequent reactiontakes from 1 to 20 hours.

Using a mixed acid anhydride method, the desired compound (I) can beprepared by reacting a compound (II) with lower alkyl halogenoformate ordi(lower alkyl) cyanophosphate to form a mixed acid anhydride and thenreacting with a compound (III).

The reaction for preparing a mixed acid anhydride is preferably carriedout by reacting a compound (II) with lower alkyl halogenoformate such asethyl chloroformate or isobutyl chloroformate of di(lower alkyl)cyanophosphate such as diethyl cyanophosphate in an inert solvent in thepresence of a base.

The bases and inert solvents to be used are the same as used in theabove acid halide method.

Although the reaction temperature depends upon the starting compound(II), the nature of the solvent and the like, the reaction is usuallycarried out at a temperature of -20° C. to 50° C. (preferably 0° C. to30° C.). The time required for the reaction depends upon the reactiontemperature and the like, but the reaction complete generally within aperiod of 1 to 24 hours.

The reaction of a mixed acid anhydride with a compound (III) ispreferably carried out in an inert solvent in the presence or absence ofa base. The bases and inert solvent to be used are the same as used inthe above acid halide method.

Although the reaction temperature depends upon the starting compound(III), the nature of the solvent and the like, the reaction is usuallycarried out at a temperature of -20° C. to 100° C. (preferably 0° C. toroom temperature). The time required for the reaction depends upon thereaction temperature and the like, but the reaction completes generallywithin a period of 1 to 24 hours.

Using a activated ester method, the desired compound (I) can be preparedby reacting a compound (II) with an agent for producing activated ester(for example, N-hydroxy compounds such as N-hydroxysuccinimide orN-hydroxybenzotriazole) in the presence of a condensing agent (forexample, dicyclohexylcarbodiimide or carbonyldiimidazole) to form anactivated ester and then reacting with a compound (III).

The reaction for preparing an activated ester is preferably carried outin an inert solvent and the solvents to be used are the same as used inthe above acid halide method.

Although the reaction temperature depends upon the starting compounds offormulae (II) and (III), the nature of the solvent and the like, thereaction for preparing an activated ester is usually carried out at atemperature of -20° C. to 50° C. (preferably -10° C. to 30° C.) and thereaction of a compound (III) with an activated ester at a temperature of-20° C. to 50° C. (preferably 0° C. to 30° C.). The time required forthe reaction depends upon the reaction temperature and the like, butboth reaction complete generally within a period of 1 to 24 hours.

Using a condensation reaction method, the desired compound of formula(I) can be prepared by reacting directly a compound (II) with a compound(III) in the presence of a condensing agent [for example,dicyclohexylcarbodiimide, carbonyldiimidazole,1-(N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride]. Thisreaction is carried out in a similar manner to the above reaction forpreparing an activated ester.

After completion of the reaction, each of the desired compounds can berecovered from the reaction mixture by conventional means. For example,one such technique comprises: collecting precipitated crystals byfiltration; or adding water; extracting with water-immiscible organicsolvent such as ethyl acetate; drying the organic extract; anddistilling off the solvent to leave the desired product behind as aresidue. If necessary, the compound produced can be purified byconventional means, for example, recrystallization, columnchromatography or the like.

The compound (I), in which the substituent involved in the definition ofR is a lower alkenyl, can be catalytically reduced to a compound inwhich the said substituent involved in the definition of R⁴ is thecorresponding alkyl group.

The catalytic reduction is carried out by contacting the correspondingalkenyl compound with hydrogen in an inert solvent in the presence of acatalyst.

Examples of the catalysts used include: for example, palladium oncharcoal, platinum oxide, rhodium on alumina and ruthenium on charcoal,preferably palladium on charcoal.

The hydrogen pressure used is, for example, ordinary pressure to 5atmospheric pressure, preferably ordinary pressure.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Examples ofthe solvents used include: for example, alcohols such as methanol orethanol; ehters such as tetrahydrofuran or dioxane; and esters such asethyl acetate; preferably ethers.

The reaction is usually carried out at a temperature of from 0° C. to100° C. (preferably room temperature to 50° C.). The time required forthe reaction depends upon the reaction temperature and the like, but thereaction completes within a period of 30 minutes to 24 hours (preferably1 to 10 hours).

After completion of the reaction, each of the desired compounds can berecovered from the reaction mixture by conventional means. For example,one such method comprises: diluting the reaction mixture with an inertsolvent such as dichloromethane; removing off the catalyst used byfiltration by the aid of Celite; and distilling off the solvent from thefiltrate to leave the desired product behind as a residue. Each of thecompounds produced can be further purified, if necessary, by suchconventional techniques as recrystallization or column chromatography.

The compound (I), in which the substituent involved in the definition ofR⁴ is an alkylthio or arylthio group, can be oxidized to give a compoundin which the substituent involved in the definition of R⁴ is thecorresponding sulfenyl or sulfonyl group.

Oxidation is carried out by contacting the corresponding alkylthio,arylthio or aralkylthio compound with an oxidizing agent in an inertsolvent in the presence of a catalyst.

Examples of the oxidizing agents used include: for example, peroxidessuch as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid,hydrogen peroxide or tert-butyl hydroperoxide, preferablym-chloroperbenzoic acid and tert-butyl hydroperoxide.

Examples of the catalysts used include: transition metal acetylacetonatesuch as vanadium acetylacetonate or molybdenum acetylacetonate,preferably vanadium acetylacetonate.

There is no particular limitation upon the nature of the solvent used,provided that it has no adverse effect upon the reaction. Examples ofthe solvents used include: for example, alcohols such as methanol orethanol; and halogenated hydrocarbons such as dichloromethane,chloroform or 1,2-dichloroethane; preferably halogenated hydrocarbons.

In order to remove acidic materials from the peroxide used, thisreaction can also be carried out in the presence of alkaline metalcarbonates such as sodium carbonate or potassium carbonate or an aqueoussolution thereof.

In this reaction, there can mainly be obtained the correspondingsulfenyl compound by using 1 to 1.5 moles of an oxidizing agent per moleof the compound (I) and there can mainly be obtained the correspondingsulfonyl compound by using 2 to 3 moles of an oxidizing agent per moleof the compound (I).

The reaction is usually carried out at a temperature of -10° C. to 80°C. (preferably 0° C. to 30° C.). Although the time required for thereaction depends upon the reaction temperature and the like, thereaction completes within a period of 30 minutes to 10 hours preferably1 to 5 hours).

After completion of the reaction, the desired compound of this reactioncan be recovered from the reaction mixture by conventional means. Forexample, the reaction mixture is freed from insoluble materials, if any,by filtration and the solvent is distilled off from the filtrate toleave the desired product behind as a residue. Alternatively, theresidue thus obtained is mixed with water and a water-immiscible organicsolvent, after which the extract is dried and the solvent is evaporatedoff to give the desired compound. The compound produced can be furtherpurified, if necessary, by such conventional techniques asrecrystallization or column chromatography.

The starting compounds (II) used in Method A are either known or caneasily be prepared in a manner known per se, for example in analogy tothe procedure described in Yakugaku Zasshi, 77, 1145(1957) and J. Org.Chem., 21, 186(1956).

Some of the compounds (II) can alternatively be prepared by thefollowing methods.

Method B ##STR7##

In the formulae given above, R¹, R² and B are as defined above; andR_(a) ³ and R_(b) ³ are the same or different and each has the samemeaning as defined for R³ excepting a hydrogen atom, provided that thecarbon numbers of R_(a) ³ and R_(b) ³ in total are not more than 6.

Method B involves the preparation of a compound (II_(a) -1), that is, acompound (II) in which R³ represents a lower alkyl, A represents amethylene group, and n is 0; a compound (II_(a) -2), that in which R³represents a hydrogen atom, A represents a formula: --CH(R_(a) ³)--(wherein R_(a) ³ is as defined above), and n is 0; a compound (II_(a)-3), that in which R³ represents a lower alkyl group A represents aformula: --CH(R_(a) ³)-- (wherein R_(a) ³ is as defined above) and n is0; and a compound (II_(a) -4), that in which R³ represents a lower alkylgroup A represents a formula: --C(R_(a) ³)(R_(a) ³)-- (wherein R_(a) ³and R_(b) ³ are as defined above), and n is 0.

Step B1 consists of the preparation of compounds of formulae (II_(a)-1), (II_(a) -2) and (II_(a) -3) by reacting a compound having a generalformula (II_(a)) with a base (for example, alkaline metal hydrides suchas lithium hydride or sodium hydride) in an inert solvent (for example,ethers such as ether or tetrahydrofuran) at a temperature of from roomtemperature to 100° C. (preferably 0° to 30° C.) for a period of from 10minutes to 3 hours (preferably 15 minutes to 1 hour) to form an alkalinemetal salt of a carboxylic acid; reacting with a base [for example,metal amides such as lithium isopropylamide, lithiumbis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide] at atemperature of from -60° C. to 50° C. (preferably -30° C. to roomtemperature) for a period of from 5 minutes to 2 hours (preferably 10minutes to 1 hour) to produce a carbanion; and finally reacting thecarbonion with a compound of a general formula: R_(a) ³ --X (IV) [whereR_(a) ³ is as defined above and X represents a halogen atom (preferablya chlorine, bromine or iodine atom)] at a temperature of from -50° C. to100° C. (preferably -50° C. to room temperature) for a period of from 15minutes to 5 hours (preferably 30 minutes to 3 hours).

Step B2 consists of the preparation of a compound (II_(a) -4) by usingas a starting compound a compound (II_(a)) and a compound of generalformula: R_(b) ³ --X (IV_(a)) (wherein R_(b) ³ and X are as definedabove) instead of a compound (IV). The reaction is carried out in asimilar manner as Step B1 given above.

The starting compounds (III) used in Method A are either known or caneasily be produced according to method known per se.

Some of the compound (III) can alternatively be produced according tothe following methods.

Method C ##STR8## Method D ##STR9##

In the formulae given above, R⁶ and R_(a) ⁶ are the same or differentand each has the same meaning as R⁴ excepting a lower alkenyl and nitrogroups of the phenyl substituents involved in the definition of R⁴ ; R⁷and R⁸ are the same or different and each represents a hydrogen atom ora lower alkyl group (provided that the carbon number of a group having aformula: --C(R⁷)═CHR⁸ in total is from 2 to 6); R⁹, R¹¹ and R¹² are thesame or different and each represents a hydrogen atom or a lower alkylgroup; and R¹⁰ represents a hydrogen atom or a C₁ -C₅ alkyl group.

Method C involves the preparation of a compound (III_(a)), that is, acompound (III) in which R⁴ represents a formula: ##STR10## (in theformula R⁶, R_(a) ⁶, R⁷ and R⁸ are as defined above) and R⁵ represents ahydrogen atom.

Step C₁ consists of the preparation of a compound of a general formula(VI) by reacting a compound (V) with a compound having general formula:

    (R.sup.13).sub.3 P.sup.⊕ --C.sup.⊖ HR.sup.8    (XI)

(in the formula, R⁸ is as defined above and R¹³ represents a C₆ -C₁₀aryl group such as a phenyl or naphthyl group) at a temperature of from0° to 50° C. (preferably about room temperature) for a period of from 30minutes to 24 hours (preferably 1 to 20 hours).

The compound (XI) can be prepared by reacting a compound of a generalformula:

    (R.sup.13).sub.3 P.sup.⊕ --CH.sub.2 R.sup.8 X.sup.⊖(XII)

with a base (for example, alkyl alkaline metals such as methyllithium,butyllithium or phenyllithium) in an inert solvent (for example, etherssuch as ether or tetrahydrofuran) at a temperature of -20° C. to 50° C.(preferably about room temperature) for a period of from 30 minutes to10 hours (preferably 1 to 5 hours).

Step C₂ involves the preparation of a compound (III_(a)) by reacting acompound (VI) with a reducing agent (for example, zinc, iron, aluminiumetc.) in an inert solvent (for example, alcohols such as methanol orethanol, or aqueous alcohols such as methanol or ethanol, or aqueousalcohol) in the presence of an acid (for example, hydrochloric acid,acetic acid etc.) or a base (for example, sodium hydroxide, potassiumhydroxide etc.) at a temperature of from room temperature to 200° C.(preferably 50° C. to 150° C.) for a period of from 30 minutes to 10hours (preferably 1 to 5 hours). The compound (III_(a)) can also beprepared from a compound (VI) by catalytic reduction and the reaction iscarried out in a similar manner as the corresponding reaction of thesaid Method A.

Method D involves the preparation of a compound of formula (III_(b)),that is, a compound (III) in which R⁴ represents a formula: ##STR11##(in the formula, R⁹, R¹⁰, R¹¹ and R¹² are as defined above) and R⁵represents a hydrogen atom.

Step D1 consists of the preparation of a compound of a general formula(VIII) by reacting a compound having a general formula (VII) with acompound of a general formula: ##STR12## (in the formula, R¹⁰, R¹¹, R¹²and X are as defined above) in an inert solvent (for example, ketonessuch as acetone or methyl ethyl ketone) in the presence of a base (forexample, alkaline metal carbonates such as sodium carbonate or potassiumcarbonate) at a temperature of from 0° to 200° C. (preferably roomtemperature to 100° C.) for a period of from 30 minutes to 5 hours(preferably 1 to 3 hours). Preferably the reaction is carried out in thepresence of a small amount of alkaline metal iodides such as sodiumiodide or potassium iodide.

Step D2 consists of the preparation of a compound of a general formula(IX) by subjecting a compound (IX) to Clasisen rearrangement in an inertsolvent (for example, diphenyl ether, N,N-dimethylaniline etc.) uponheating at a temperature of from 50° C. to 250° C. (preferably 100° C.to 200° C.) for a period of from 30 minutes to 15 hours (preferably 1 to10 hours).

Step D3 consists of the preparation of a compound of a general formula(X) by reacting a compound (IX) with an acid (for example, Lewis acidssuch as boron trifluoride, boron trifluoride etherate or magnesiumchloride, proton acids such as 47% hydrobromic acid-acetic acid etc.) inan inert solvent (for example, halogenated hydrocarbons such asdichloromethane or chloroform) at a temperature of from 0° to 50° C.(preferably about room temperature) for a period of from 30 minutes to10 hours (preferably 1 to 5 hours).

Step D4 consists of the preparation of a compound (III_(b)) by reducinga compound (X) in a similar manner as the said Step B1 of Method B.

In each of these steps, the desired compound can be recovered from thereaction mixture according to conventional means. An example of one suchtechnique comprises: filtering the reaction mixture if insolublematerials exist; neutralizing properly if the reaction mixture is acidicor basic; distilling off the solvent; adding water to the residue thusobtained; extracting with a water-immiscible organic solvent; drying theorganic extract; and finally distilling off the solvent. If necessary,the products can be further purified by conventional means, for example,recrystallization, column chromatography or the like.

Effect of the Invention

As can be seen from the following Test Example, the compounds (I) of theinvention have an excellent ACAT inhibiting activity and show a lowtoxicity. Accordingly, they are useful for the treatment and prophylaxisof atherosclerosis.

TEST EXAMPLE 1 ACAT Inhibiting Effect

ACAT inhibiting activities were determined according to the improvedtest method in vitro reported by Ross et al. [A. C. Ross etal., J. Biol.Chem., 259, 815-819(1984)].

According to the procedure described in A. C. Ross et al., J. Biol.Chem., 257, 2453-2459(1982), rat liver microsome was prepared from a ratof Sprague-Dawley strain fasted overnight to make an enzyme fraction. Toa 0.15M potassium phosphate buffer solution (pH 7.4) containing 100 μMof [14C]oleoyl-CoA, 2 mM of dithiothreitol and 80 μM of bovine serumalbumin were added 60-100 μg of the microsome fraction, and a 5 μlsolution of a test compound in dimethylsulfoxide (2.5% v/v) was added tothe above phosphate buffer solution to make 200 μl. The mixture waswarmed at 37° C. for 4 minutes and then the enzyme reaction was stoppedby adding 1 ml of ethanol under stirring. To the reaction mixture wereadded 2 ml of hexane. After stirring, 1 ml of a hexane solution wastaken out and the solvent was evaporated in a stream of nitrogen.Cholesteryl oleate resulted from the enzyme reaction was separated bythin layer chromatography through silica gel using a 85:15:1 mixture ofhexane, diethyl ether and acetic acid as a developing solvent. An ACATactivity was determined by measuring radioactivity and a inhibiting rate(%) was calculated by comparing a control activity with that of the testcompound at given concentrations.

Compounds of Examples 1, 2, 3, 9, 10, 11, 16, 18-B and 25 were evaluatedas having an excellent inhibiting activity.

For the treatment or prophylaxis of atherosclerosis the compounds (I)are administered alone or as a pharmaceutical composition in admixturewith one or more carriers, excipients and/or diluents. They can beadministered orally in the form of powders, granules, tablets, capsulesetc. or parenterally by injection etc. The dose varies depending uponthe condition of the patient and upon the route and type ofadministration but, in general, the compounds of the invention can beadministered orally at one-time dose of from 1 to 2000 mg, particularly5 to 300 mg, or intravenously at one-time dose of from about 0.1 to 100mg, particularly 0.5 to 50 mg once to thrice a day.

The present invention is explained in detail by the following Examplesand Referential Examples. Such examples are not to be construed as beinglimitative of the invention.

EXAMPLES Example 1 N-[2,6-Bis(1-methylethyl)phenyl]-2-(9H-xanthen-9-yl)acetamide

To a solution of 51 mg (0.21 mmol) of 2-(9H-xanthen-9yl)acetic acid in 2ml of dichloromethane were added 0.1 ml (1.1 mmol) of oxalyl chlorideand one drop of N,N-dimethylformamide with ice-cooling, and theresulting mixture was stirred for 3 hours and freed from the solvent andan excess of the reagent by distillation under reduced pressure. Theresidue was again dissolved in 2 ml of dichloromethane, and 93 mg (0.53mmol) of 2,6-bis(1-methylethyl)aniline and 0.2 ml of pyridine were addedthereto with ice-cooling, followed by stirring at room temperature for 5hours. After distilling off the solvent, the residue thus obtained waspurified by column chromatography through 15 g of silica gel using a30:0-1 mixture of dichloromethane and ethyl acetate as an eluent to give78 mg (92%) of the desired compound as crystals.

m.p. 231°-232.5° C. (recrystallized from ethyl acetate).

IR spectrum (KBr) cm⁻¹ : 3253, 1651, 1517, 1481, 1457, 1259, 757.

NMR spectrum (CDCl₃) ppm: 1.05 (6H, d, J=7 Hz), 2.27 (2H, septet, J=7Hz), 2.78 (2H, d, J=7 Hz), 4.73 (1H, t, J=7 Hz), 6.3-6.5 (1H, br.s),6.8-7.5 (11H, m).

Example 2 N-(2,6-Diethylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using 2,6-diethylanillineinstead of 2,6-bis(1-methylethyl)aniline, there was obtained the titlecompound in 83% yield.

m.p. 228.5°-229.5° C.

IR spectrum (KBr) cm⁻ : 1646, 1523, 1481, 1261, 753.

Example 3 N-(2-Ethyl-6-methylthiomethylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-ethyl-6-methylthiomethylaniline instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in62% yield.

m.p. 122°-123° C.

IR spectrum (KBr) cm⁻¹ : 1648, 1514, 1480, 1458, 1258.

Example 4 N-(2-Butoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using 2-butoxy-6-vinylanilineinstead of 2,6-bis(1-methylethyl)aniline, there was obtained the titlecompound in 64% yield.

m.p. 176°-177° C.

IR spectrum (KBr) cm⁻¹ : 1655, 1533, 1481, 1260, 754.

Example 5 N-(2-Methoxy- 6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using 2-methoxy-6-vinylaniline(a compound of Referential Example 1) instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in28% yield.

m.p. 230.5°-231° C.

IR spectrum (KBr) cm⁻¹ : 1653, 1528, 1482, 1262, 754.

Example 6 N(2-Isopropoxy-6-vinylphenyl)-2-(9H- xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-isopropoxy-6-vinylaniline instead of 2,6-bis(1-methylethyl)aniline,there was obtained the title compound in 63% yield.

m.p. 171.5°-172° C.

IR spectrum (KBr) cm⁻¹ : 1654, 1530, 1481, 1260, 752.

Example 7 N-(2,4,6-Trimethoxyphenyl)-2-(9H -xanthen-9-yl)acetamide

Following the procedure of Example 1, but using 2,4,6-trimethoxyanilineinstead of 2,6-bis(1-methylethyl)aniline, there was obtained the titlecompound in 82% yield.

m.p. 223°-224° C.

IR spectrum (KBr) cm⁻¹ : 1655, 1537, 1261, 1136, 755.

Example 8 N-(2-Benzyloxy-6-nitrophenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-benzyloxy-6-nitroaniline instead of 2,6-bis(1-methylethyl)aniline,there was obtained the title compound in 14% yield.

m.p. 200°-200.5° C. IR spectrum (KBr) cm⁻¹ : 1669, 1550, 1514, 1362,1261. Example 9N-(2-Ethyl-6-methylthiophenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-ethyl-6-methylthioaniline instead of 2,6-bis(1-methylethyl)aniline,there was obtained the title compound in 63% yield.

m.p. 139°-140° C. IR spectrum (KBr) cm⁻¹ : 1649, 1516, 1481, 1457, 1258.Example 10N-(2-Ethyl-6-isopropylthiophenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-ethyl-6-isopropylaniline instead of 2,6-bis(1-methylethyl)aniline,there was obtained the title compound in 89% yield.

m.p. 184.5°-186° C.

IR spectrum (Nujol) cm⁻¹ : 1648, 1518, 1482, 1260, 760.

Example 11 N-(2- Ethyl -6-phenylthiophenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-ethyl-6-phenylthiophenylaniline instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in69% yield.

m.p. 237°-239° C.

IR spectrum (Nujol) cm⁻¹ : 1648, 1518, 1482, 1260, 760.

Example 12 N-(2-Methylthio-6-methoxymethylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-methylthio-6-methoxymethylaniline instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in40% yield.

m.p. 231°-232° C.

IR spectrum (KBr) cm⁻¹ : 1649, 1519, 1481, 1261, 1114, 758.

Example 13 N-(2-Chloro-6-methoxycarbonylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-chloro-6-methoxycarbonylaniline instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in26% yield.

m.p. 178°-179° C.

IR spectrum (KBr) cm⁻¹ : 1729, 1665, 1516, 1481, 1292, 761.

Example 14 N-(6-Ethyl-2,3-dihydro-2-methylbenzo[b]furan-7-yl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using7-amino-6-ethyl-2,3-dihydro-2-methylbenzo[b]furan (a compound ofReferential Example 2) instead of 2,6-bis(1-methylethyl)aniline, therewas obtained the title compound in 62% yield.

m.p. 278°-279° C.

IR spectrum (Nujol) cm⁻¹ : 1653, 1540, 1378, 1262, 765.

Example 15N-(6-Methyl-2,3-dihydro-2-methylbenzo[b]furan-7-yl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using7-amino-6-methyl-2,3-dihydro-2-methylbenzo[b]furan instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in74% yield.

m.p. 290 °-291° C.

IR spectrum (Nujol) cm⁻¹ : 1650, 1538, 1378, 1262, 760.

Example 16N-[2,6-Bis(1-methylethyl)phenyl]-2-(9H-xanthen-9-yl)propanamide

Following the procedure of Example 1, but using2-(9H-xanthen-9-yl)propionic acid instead of 2-(9H-xanthen-9-yl)aceticacid, there was obtained the title compound in 67% yield.

m.p. 209.5°-211° C.

IR spectrum (KBr) cm⁻¹ : 1644, 1516, 1456, 1257, 757.

Example 17 N-[2,6-Bis(1-methylethyl)phenyl]-2-(9H-xanthen-9yl)hexanamide

Following the procedure of Example 1, but using2-(9H-xanthen-9-yl)hexanoic acid instead of 2-(9H-xanthen-9-yl)aceticacid, there was obtained the title compound in 22% yield.

m.p. 188°-189° C.

IR spectrum (KBr) cm⁻¹ : 1655, 1504, 1475, 1250, 751.

Example 18N-[2,6-Bis(1-methylethyl)phenyl]-2-(9-methyl-9H-xanthen-9-yl)propanamide(Compound A) andN-[2,6-bis(1-methylethyl)phenyl]-2-(9-methyl-9H-xanthen-9-yl)acetamide(Compound B)

Following the procedure of Example 1, but using a mixture of 2-(9-methyl-9H-xanthen-9-yl)propionic acid, 2-(9-methyl-9H-xanthen-9-yl)acetic acidand 2-(9H-xanthen-9-yl)propionic acid prepared in Referential Example 3instead of 2-(9H-xanthen-9-yl)acetic acid, there was obtained the titlecompound after purifying by column chromatography through silica gelusing a 1:8 mixture of ethyl acetate and hexane, and dichloromethane asan eluent.

Compound A

Yield: 32%.

m.p. 140°-141° C.

IR spectrum (KBr) cm⁻¹ : 1659, 1501, 1474, 1456, 1246.

Compound B

Yield: 37%.

m.p. 151°-152° C.

IR spectrum (KBr) cm⁻¹ : 1653, 1512, 1484, 1455, 1438, 1265.

In this reaction, there was also obtained a compound of Example 16 in10% yield.

Example 19 N-(2,6-Dimethylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using 2,6-dimethylanilineinstead of 2,6-bis(1-methylethyl)aniline, there was obtained the titlecompound in 75% yield.

m.p. 249°-250° C.

IR spectrum (KBr) cm⁻¹ : 1648, 1526, 1481, 1263, 755.

Example 20N-[2,6-Bis(1-methylethyl)phenyl]-2-methyl-2-(9-methyl-9H-xanthen-9-yl)propanamide

Following the procedure of Example 1, but using2-methyl-2-(9-methyl-9H-xanthen-9-yl)propanoic acid instead of2-(9H-xanthen-9-yl)acetic acid to form the corresponding acid chlorideand reacting the acid chloride with 2,6-bis(1-methylethyl)aniline in1,2-dichloroethane for 16 hours in the presence ofN,N-dimethyl-4-aminopyridine (an equivalent) and pyridine (10equivalents) under refluxing followed by working-up in a similar manneras Example 1, there was obtained the title compound in 45% yield.

m.p. 182°-183° C.

IR spectrum (KBr) cm⁻¹ : 1644, 1491, 1471, 1442, 1243.

Example 21N-[2,6-Bis(1-methylethyl)phenyl]-2-[(9H-xanthen-9-yl)thio]acetamide

Following the procedure of Example 1, but using2-[(9H-xanthen-9-yl)thio]acetic acid instead of2-(9H-xanthen-9-yl)acetic acid, there was obtained the title compound in51% yield.

m.p. 213°-214. 5° C.

IR spectrum (Nujol) cm⁻¹ : 1655, 1518, 1380, 1258, 760.

Example 22N-[2,6-Bis(1-methylethyl)phenyl]-2-(2-chloro-9H-thioxanthen-9-yl)]acetamide

Following the procedure of Example 1, but using2-[(9H-thioxanthen-9-yl)thio]acetic acid instead of2-(9H-xanthen-9-yl)acetic acid, there was obtained title compound in 81%yield.

m.p. 224°-225° C.

IR spectrum (KBr) cm⁻¹ : 1650, 1531, 1464, 737.

Example 23 N-(2- Ethyl -6-methoxyphenyl)-2-(9H-xanthen-9-yl)acetamide

A solution of 258 mg (0.62 mmol) ofN-(2-methoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide in 54 ml oftetrahydrofuran was vigorously stirred at room temperature for 10 hoursin the presence of 20 mg of 10% palladium on charcoal in a stream ofhydrogen. The reaction mixture was filtered with the aid of Celite andthe catalyst was washed with tetrahydrofuran. The filtrate and thewashings were combined and concentrated. The residue was recrystallizedfrom a mixture of dichloromethane and hexane to give 99 mg (57%) of thetitle compound as crystals.

m.p. 238°-239° C.

IR spectrum (KBr) cm⁻¹ : 1652, 1528, 1482, 1261, 754.

NMR spectrum (CDCl₃) δ ppm:

0.89 (2/3H,t, J=7.5 Hz), 1.11 (7/3H, t, J=7.5 Hz), 2.12 (4/9H, br.),2.31 (4/9H, br.d, J=7 Hz), 2.46 (14/9H, q, J=7.5 Hz), 2.75 (14/9H, d,J=7 Hz), 3.55 (2/3H, s), 3.68 (7/3H, s), 4.72 (1H, t J=7 Hz), 6.38(2/9H, s), 6.46 (7/9H, s), 6.63 (2/9H, d, J=8 Hz), 6.70 (7/9H, d, J=8Hz), 6.85 (7/9H, d, J=8 Hz), 6.99-7.37 (51/7H, m), 7.39 (2H, d, J=6 Hz).

Example 24 N-(2-Ethyl-6-butoxyphenyl)-2-9H-xanthen-9-yl)acetamide

Following the procedure of Example 23, but usingN-(2-butoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide instead ofN-(2-methoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide, there wasobtained the title compound in 92% yield.

m.p. 195°-196° C.

IR spectrum (KBr) cm⁻¹ : 1650, 1529, 1481, 1461, 753.

Example 25 N-(2-Ethyl -6-isopropoxyphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 23, but usingN-(2-isoporpoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide instead ofN-(2-methoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide, there wasobtained the title compound in 57% yield.

m.p. 185-186° C.

IR spectrum (KBr) cm⁻¹ : 1653, 1528, 1480, 1260, 754.

Example 26 N-(2-Ethyl-6-methylsulfonylphenyl)-2-(9H-xanthen-9-yl)acetamide (Compound A) andN-(2-ethyl-6-methylsulfinylphenyl)-2-(9H -xanthen-9-yl)acetamide(Compound B)

To a suspension of 100 mg (0.26 mmol) ofN-(2-ethyl-6-methylthiophenyl)-2-(9H-xanthen-9-yl)acetamide in 3 ml ofdichloromethane were added 0.56 ml of a 1N aqueous solution of sodiumhydrogencarbonate and then 95 mg (0.39 mmol) of 70% m-chloroperbenzoicacid with ice-cooling, and the resulting mixture was stirred at the sametemperature for 40 minutes. The reaction mixture was diluted with etherand the ethereal layer was washed with water followed by distilling offthe solvent. The residue was purified by column chromatography through10 g of silica gel using a 12:1 mixture of dichloromethane and ethylacetate as an eluent to give 68 mg (63%) of a methylsulfonyl derivative(Compound A). The column was further eluted with a 1:2 mixture ofdichloromethane and ethyl acetate to give 25 mg (24%) of amethylsulfinyl derivative (Compound B).

Compound A

m.p. 195°-196° C. (recrystallized from a mixture of dichloromethane andhexane).

IR spectrum (KBr) cm⁻¹ : 1650, 1535, 1481, 1457, 1314, 1261.

NMR spectrum (CDCl₃) δ ppm: 1.18 (3H, t, J=7.5 Hz), 2.53 (2H, q, J=7.5Hz), 2.55 (3H, s), 2.85 (2H, d, J=7 Hz), 4.71 (1H, t, J=7 Hz), 7.05 (2H,t, J=8 Hz), 7.15 (2H, d, J=8 Hz), 7.24 (2H, t, J=8 Hz), 7.38 (2H, d, J=8Hz), 7.39 (1H, t, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.80 (1H, d, J=8 Hz).

Compound B

IR spectrum (CHCl₃) cm⁻¹ : 1665, 1515, 1480, 1458, 1255, 1028.

NMR spectrum (CDCl₃) δ ppm: 1.05 (3H, t, J=7.5 Hz), 2.32 (2H, q, J=7.5Hz), 2.57 (3H, s), 2.75 (1H, dd, J=7.5, 15 Hz), 2.80 (1H, dd, J=6.5, 15Hz), 4.65 (1H, dd, J=6.5, 7.5 Hz), 7.02-7.14 (4H, m), 7.20-7.38 (6H, m),7.48-7.52 (1H, m), 8.09 (1H, m, br.s).

Example 27N-(2-Chloro-6-methoxymethylphenyl)-2-(9H-xanthen-9-yl)acetamide

Following the procedure of Example 1, but using2-chloro-6-methoxymethylaniline instead of2,6-bis(1-methylethyl)aniline, there was obtained the title compound in49% yield.

m.p. 184°-185° C.

IR spectrum (KBr) cm⁻¹ : 1651, 1522, 1480, 1455, 757.

Reference Example 1 2-Methoxy-6-vinylaniline a)2-Methoxy-6-vinyl-1-nitrobenzene

A suspension of 4.35 g (12.2 mmol) of triphenylmethylphosphonium bromidein 30 ml of tetrahydrofuran was cooled to -10° C. and 12.1 mmol of a1.44M solution of butyllithium were dropwise added thereto over a periodof 5 minutes. After the resulting mixture was stirred at 0° C. for 40minutes, a solution of 1.99 g (11.0 mmol) of3-methoxy-2-nitrobenzaldehyde in 10 ml of tetrahydrofuran was dropwiseadded thereto over a period of 10 minutes. The temperature of thereaction mixture was allowed to rise to room temperature. After stirringfor 16 hours, the reaction mixture was poured into an aqueous solutionof ammonium chloride followed by extracting with ether. The etherealextract was washed with a saturated aqueous solution of sodium chlorideand the solvent was distilled off. The residue was purified by columnchromatography through 100 g of silica gel using a 15-20:100 mixture ofethyl acetate and hexane as an eluent to give 1.50 g (76%) of the titlecompound.

m.p. 55°-56° C. (recrystallized from a mixture of ethyl acetate andhexane).

IR spectrum (Nujol) cm⁻¹ : 1576, 1528, 1373, 1280, 1065.

NMR spectrum (CDCl₃) δ ppm: 3.86 (3H, s), 5.45 (1H, dd, J=2, 11 Hz),5.80 (1H, dd, J=2, 18 Hz), 6.66 (1H, dd, J=11, 18 Hz), 6.88-7.55 (3H,m).

b) 2-Methoxy-6-vinylaniline

A mixture of 500 mg (2.8 mmol) of the compound prepared in ReferentialExample 1(a), 0.46 ml of a 20% aqueous solution of sodium hydroxide and7 ml of ethanol was heated under refluxing for an hour and a half. Thereaction mixture was filtered by the aid of Celite and insolublematerials were washed with ethanol. The filtrate and the washings werecombined and the solvent was distilled off. The residue was partitionedbetween a 2:1 mixture of ethyl acetate and hexane, and water. Theorganic layer was washed with water and the solvent was distilled off.The residue was purified by column chromatography through 8 g of silicagel using a 1:1 mixture of dichloromethane and hexane as an eluent togive 366 mg (88%) of the title compound as an oil.

NMR spectrum (CDCl₃) δ ppm: 3.6-4.3 (2H, br.s), 3.84 (3H, s), 5.1-5.3(1H, m), 5.3-5.6 (1H, m), 5.7-5.8 (1H, m), 6.5-7.1 (3H, m).

Reference Example 2 7-Amino-6-ethyl-2,3-dihydro-2-methylbenzo[b]furan a)2-Allyloxy-6-ethyl-1-nitrobenzene

A mixture consisted of 3.15 g (18.2 mmol) of2-ethyl-6-hydroxy-1-nitrobenzene, 4.44 g (36.7 mmol) of allyl bromide,2.70 g (19.5 mmol) of potassium carbonate, 262 mg (1.75 mmol) of sodiumiodide and 30 ml of acetone was heated under refluxing for 2 hours.After cooling, the reaction mixture was diluted with ether and thediluted mixture was filtered to remove inorganic substances. Thefiltrate was concentrated and the concentrate was purified by columnchromatography through 150 g of silica gel using a 1:9 mixture of etherand hexane as an eluent to give 3.68 g (98%) of the title compound as anoil.

IR spectrum (Liq) cm⁻¹ : 1612, 1582, 1530, 1372, 1280.

NMR spectrum (CDCl₃) ppm: 1.21 (3H, t, J=7 Hz), 2.59 (2H, q, J=7 Hz),4.52-4.65 (2H, m), 5.13-5.58 (2H, m), 5.72-6.34 (1H, m), 6.78-6.96 (2H,m), 7.21-7.49 (1H, m).

b) 3-Allyl-6-ethyl-2-hydroxy-1-nitrobenzene

A solution of 807 mg (3.88 mmol) of the compound prepared in ReferentialExample 2(a) in 2 ml of diphenyl ether was heated at 180° C. for 5hours. The reaction mixture was cooled and diluted with ether. Thediluted mixture was extracted with a 2N aqueous solution of sodiumhydroxide and the aqueous extract was acidified by 2N hydrochloric acidfollowed by extracting with ether. The ethereal extract was washed witha saturate aqueous solution of sodium chloride and the solvent wasdistilled off. The residue was purified by column chromatography through25 g of silica gel using a 5:95 mixture of ether and hexane as an eluentto give 583 mg (73%) of the title compound as an oil.

IR spectrum (Liq) cm⁻¹ : 3350, 1640, 1607, 1588, 1543, 1420.

NMR spectrum (CDCl₃) δ ppm: 1.22 (3H, t, J=7 Hz), 2.89 (2H, q, J=7 Hz),3.42 (2H, d, J=6 Hz), 4.90-5.32 (2H, m), 5.68-6.36 (1H, m), 6.80 (1H, d,J=8 Hz), 7.31 (1H, d, J=8 Hz), 10.31 (1H, s).

c) 7-Amino-6-ethyl-2,3-dihydro-2-methylbenzo[b]furan

To a solution of 581 mg (2.80 mmol) of the compound prepared inReferential example 2(b) in 6 ml of dichloromethane was dropwise added0.70 ml (5.6 mmol) of boron trifluoride etherate with ice-cooling, andthe resulting mixture was stirred at room temperature for 3 hours. Thereaction was stopped by adding a saturated aqueous solution of sodiumhydrogencarbonate and the reaction mixture was extracted with ether. Theethereal extract was subsequently washed with a 2N aqueous solution ofsodium hydroxide, water and a saturated aqueous solution of sodiumchloride and the solvent was distilled off. The residue (202 mg)containing a ring-closed compound was dissolved in methanol and thesolution was vigorously stirred at room temperature for 50 minutes in astream of hydrogen in the presence of 27 mg of 10% palladium oncharcoal. The reaction mixture was filtered by the aid of Celite and thecatalyst was washed methanol. The filtrate and the washings werecombined and the solvent was distilled off. The residue was purified bycolumn chromatography through 20 g of silica gel using a 1:4 mixture ofether and hexane as an eluent to give 129 mg (26%) of the title compoundas an oil.

IR spectrum (Liq) cm⁻¹ : 3470, 3380, 1635, 1608, 1495, 928.

NMR spectrum (CDCl₃) δ ppm: 1.22 (3H, t, J=7 Hz), 1.45 (3H, d, J=6 Hz),2.48 (2H, q, J=7 Hz), 2.75 (1H, dd, J=8, 15 Hz), 3.25 (1H, dd, J=8, 15Hz), 2.9-4.0 (2H, br.s), 4.90 (1H, tq, J=8, 6 Hz), 6.59 (2H, s).

Reference Example 3 2-(9-Methyl-9H-xanthen-9-yl)propionic acid (CompoundA), 2-(9-methyl-9H-xanthen-9-yl)acetic acid (Compound B) and2-(9H-xanthen-9-yl)propionic acid (Compound C)

To a suspension of 55 mg (1.26 mmol) of sodium hydride previously washedwith n-hexane in 5 ml of tetrahydrofuran were added 316 mg (3.13 mmol)of diisopropylamine, and then a solution of 300 mg (1.25 mmol) of2-(9H-xanthen-9-yl)acetic acid in 4 ml of tetrahydrofuran was dropwiseadded thereto. After completion of the addition, the resulting mixturewas heated under refluxing for 20 minutes and then cooled to -15° C.,after which 1.2 ml (1.9 mmol) of a 1.6M n-butyllithium solution wereadded thereto followed by stirring at the same temperature for 15minutes. To the mixture was dropwise added a solution of 531 mg ofmethyl iodide in 2 ml of tetrahydrofuran over a period of 10 minutes,after which stirring was continued at the same temperature for an hour.With ice-cooling the reaction was stopped by addition of a dilutedaqueous solution of sodium hydrogencarbonate and the reaction mixturewas washed with dichloromethane. The aqueous layer separated wasacidified with concentrated hydrochloric acid and extracted twice withether. The combined ether extracts were subsequently washed with waterand a saturated aqueous solution of sodium chloride and the solventdistilled off to give a mixture of the titled Compound A, B and C. Themixture thus obtained was used in the following reaction withoutpurification.

We claim:
 1. A tricyclic heterocyclyl compound having the followingformula: ##STR13## wherein, R³ represents a hydrogen atom or a loweralkyl group;R⁴ represents a phenyl group which has 2 substituents,wherein one of the substituents is at the 2-position and the other is atthe 6-position and the substituents are individually selected from thegroup consisting of a lower alkyl, a lower alkoxy(lower alkyl), a loweralkylthio(lower alkyl), a lower alkoxy, a lower alkylthio, a loweralkenyl, an arylthio and a lower alkylsulfonyl; R⁵ represents a hydrogenatom or a lower alkyl group; and A represents a lower alkylene group. 2.A compound according to claim 1 wherein each said substituents isselected from the group consisting of C₁ -C₄ alkyl, C₁ -C₄ alkoxy-(C₁-C₄ alkyl), C₁ -C₄ alkylthio (C₁ -C₄ alkyl), C₁ -C₄ alkoxy, C₁ -C₄alkylthio, C₂ C₄ alkenyl, C₆ C₁₀ arylthio and C₁ -C₄ alkylsulfonyl.
 3. Acompound according to claim 2 wherein the substituents are selected fromthe group consisting of ethyl, isopropyl, isopropylthio,methylthiomethyl, vinyl, methylthio, phenylthio, methoxymethyl,isopropoxy, and methylsulfonyl.
 4. A compound according to claim 2wherein the substituents are selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, methoxylmethyl, methoxyethyl,ethoxymethyl, ethoxyethyl, methylthiomethyl, methylthioethyl,ethylthiomethyl, ethylthioethyl, vinyl, allyl, methoxy, ethoxy propoxy,isopropoxy, methylthio, ethylthio, propylthio, isopropylthio andphenylthio.
 5. A compound according to claim 1, wherein R³ represents ahydrogen atom or a methyl or ethyl group.
 6. A compound according toclaim 1, wherein R³ represents a hydrogen atom or a methyl group.
 7. Acompound according to claim 1, wherein R⁵ represents a hydrogen atom, amethyl or ethyl group.
 8. A compound according to claim 1, wherein R⁵represents a hydrogen atom.
 9. A compound according to claim 1, whereinA represents a C₁ -C₄ alkylene group.
 10. A compound according to claim1, wherein A represents a C₁ -C₂ alkylene group.
 11. A compoundaccording to claim 2, wherein:R³ represents a hydrogen atom, a methyl orethyl group; R⁵ represents a hydrogen atom, a methyl or ethyl group; andA represents a C₁ -C₄ alkylene group.
 12. A compound according to claim3, wherein:R³ represents a hydrogen atom, a methyl or ethyl group; R⁵represents a hydrogen atom, a methyl or ethyl group; and A represents aC₁ -C₄ alkylene group.
 13. A compound according to claim 3, wherein:R³represents a hydrogen atom, a methyl or ethyl group; R⁵ represents ahydrogen atom, a methyl or ethyl group; and A represents a C₁ -C₄alkylene group.
 14. A compound according to claim 4, wherein:R³represents a hydrogen atom or a methyl group; R⁵ represents a hydrogenatom; and A represents a C₁ -C₂ alkylene group.
 15. A compound accordingto claim 1, wherein:R³ represents a hydrogen atom or a methyl group; R⁵represents a hydrogen atom; and A represents a C₁ -C₂ alkylene group.16. A therapeutic composition for atherosclerosis comprising a compoundselected from the compounds according to claim 1 in admixture with apharmaceutically acceptable carrier or vehicle.
 17. A therapeuticcomposition for atherosclerosis comprising a compound selected from thecompounds according to claim 11 in admixture with a pharmaceuticallyacceptable carrier or vehicle.
 18. A therapeutic composition foratherosclerosis comprising a compound selected from the compoundsaccording to claim 12 in admixture with a pharmaceutically acceptablecarrier or vehicle.
 19. A therapeutic composition for atherosclerosiscomprising a compound selected from the compounds according to claim 13in admixture with a pharmaceutically acceptable carrier or vehicle. 20.A therapeutic composition for atherosclerosis comprising a compoundselected from the compounds according to claim 14 in admixture with apharmaceutically acceptable carrier or vehicle.
 21. A therapeuticcomposition for atherosclerosis comprising a compound selected from thecompounds according to claim 15 in admixture with a pharmaceuticallyacceptable carrier or vehicle.